Women who have had a stroke or a transient ischemic attack were more likely than men to have a history of stroke in mothers than in fathers and in sisters than in brothers, according to a report published online in the Dec. 22 issue of Lancet Neurology.

The findings emerged from a study of strokes in mother, father, and other first-degree relatives of men and women with ischemic stroke or TIA in the population-based Oxford Vascular Study (OXVASC). The OXVASC study assessed all incident or recurrent TIAs and strokes among 91,106 patients registered with 63 family physicians in Oxfordshire in England.

The study included 806 patients (423 women, 383 men). Compared with the men, the women were older, were slightly more likely to have had a TIA as a qualifying event, and were more likely to have a history of hypertension, to be a lifetime non-smoker, and to have had high mean cholesterol concentrations, the researchers reported.

The study's findings were independent of traditional risk factors and stroke subtype and were:

Women were more likely than men to have at least one affected first-degree relative (146/423 women versus 104/383 men; OR 1.4, 95% CI 1.1-2.0, P=0.02), due entirely to an excess of affected female relatives of female participants (female relative versus male relative OR=1.7, 1.3 to 2.4, P= 0.0004).

Maternal stroke was almost twice as common as paternal stroke in the parents of women subjects (OR =1.8, CI 1.2-2.7, P=0.001), but not so for men (OR= 1.1, CI 0.7-1.7, P=1.7).

Female participants were three times more likely than men to have an affected sister (OR= 3.1, CI 1.5-6.7, P=0.004) but not an affected brother (OR 1.1, CI 0.6-2.1, P= 0.80).

Age of first stroke also correlated within families among affected women but not affected men, such that the excess of affected female relatives of female subjects was greatest when the age difference at the first stroke was less than five years (OR=3.7, CI 1.6-8.6, P= 0.0007). The relationship declined as the age difference increased (P for trend=0.004).

These findings were confirmed in two independent data sets, which showed an excess maternal history of strokes in female participants (OR=2.3, CI 1.5-3.8, P<0.00001) and the lack in men (OR=1.0, CI 0.7-1.4, P=0.58).

Using OXAVASC data, the researchers also found that their results were consistent across age groups, were independent of intermediate phenotypes, and were not present for family history of myocardial infarction.

Genetic and non-genetic factors may explain the findings. Mitochondrial transmission of a genetic profile is a possibility, the researchers suggested. Also, they said epigenetic phenomenon, changes in gene expression that do not entail a change in DNA sequence factors, could play a role. Another possibility is genomic imprinting, a subtype of epigenetic regulation in which gene activity is modified depending on the sex of the parent.

There could also be non-genetic explanations, the researchers postulated. Mothers, daughters, and sisters could share environmental risk factors for stroke. No relation to traditional risk factors was found, but other factors, might come into play, such as those relating to childhood socioeconomic or psychological environment. Of note, they said, fetal or early-life programming and response to stress are likely to be related to epigenetic modifications.

Limitations of the study included the possibility of receiving an inaccurate family history from patients or relatives, especially regarding diagnosis in their parents. Furthermore, women may have reported family history more accurately than men.

It has also been suggested that "don't know" responses from male subjects indicating no family history may have produced a bias, although such responses were rare in the study and were slightly more common among women.

First, the data direct future research toward potential genetic, epigenetic, and non-genetic factors that could affect the increased heritability of stroke in women.

Also, linkage or association studies could be more powerful if families with affected members were analyzed separately, they said. The fact that previous genetic association studies of stroke have not considered sex-specific transmission might explain inconsistent results.

Finally, the investigators said, this study identifies family history of stroke in a female first-degree relative as being an important clinical indicator of an increased risk of stroke in women and the likely age of the first event.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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